Category Archives: Parkinson’s Disease

Phenylpropionamides of Cannabis sativa L. seeds exert a cytoprotective effect through modulation of the AMPK/mTOR/ULK1 autophagy pathway and attenuate apoptosis in MPP+-induced SH-SY5Y cells

Posted on by

“Objective: This study aimed to investigate whether phenylpropionamides (PHS) exert therapeutic effects on Parkinson’s disease (PD) by targeting autophagy-related pathways, using network pharmacology and in vitro experiments.

Methods: Network pharmacology (NP) analysis and molecular dynamics simulation (MDS) were applied to elucidate the potential mechanisms by which PHS treats PD. Subsequently, SH-SY5Y cells were treated with MPP+ to establish a neurotoxin model. Cell viability was assessed using the CCK-8 assay. Mitochondrial membrane potential (MMP) in SH-SY5Y cells was measured using JC-1 staining. Western blot (WB) was used to detect the expression of Bax, cleaved caspase-3, caspase-3, LC3-II, p62, Beclin-1, AMPK, mTOR, and ULK1 signaling proteins in SH-SY5Y cells.

Results: NP analysis suggested that the potential anti-PD effects of PHS were associated with cleaved caspase-3, Bcl-2, mTOR, and Beclin-1. Furthermore, KEGG and PPI analyses demonstrated that PHS may exert anti-PD effects by modulating the AMPK/mTOR/ULK1 autophagy signaling pathway. Molecular docking (MolD) and MDS showed that the key PHS component (Cannabisin I) had a stable interaction with caspase-3, Bcl-2, AMPK, mTOR, ULK1, and Beclin-1. The in vitro experiments showed that PHS suppressed the expression of cleaved caspase-3 and Bax, promoted Bcl-2 expression, activated the autophagy pathway, increased the levels of LC3-II and Beclin-1, increased mitochondrial membrane potential and decreased the levels of p62. Notably, PHS promoted autophagy by increasing AMPK and ULK1 while inhibiting mTOR protein levels. Therefore, PHS may represent a promising candidate for neuroprotective intervention in neurodegenerative disorders.

Conclusion: This study suggests that PHS may exert anti-PD effects, possibly through triggering autophagy via the AMPK/mTOR/ULK1 signaling pathway.”

https://pubmed.ncbi.nlm.nih.gov/42456387

“Historically, the seeds of Cannabis sativa L. have been used in traditional Chinese medicine (TCM). They are frequently utilized in various dietary applications, including cannabis seed oil, bread, and yogurt. Because they are rich in unsaturated fatty acids (UFAs) and essential amino acids (EAAs), they have been sought after by people. In addition, they have been reported to exhibit neuroprotective and immunomodulatory effects, as well as benefits for gastrointestinal health.

Furthermore, UFAs and EAAs, the seeds of Cannabis sativa L., are abundant in a category of compounds known as phenylpropionamides (PHS). Research has demonstrated that PHS compounds possess the ability to inhibit apoptosis in the SH-SY5Y cell model of PD, which is triggered by 1-methyl−4-phenylpyridinium (MPP+), by modulating the autophagy pathway. Previous studies have identified 22 PHS in cannabis seeds and demonstrated that PHS ameliorated MPTP-induced PD symptoms by promoting autophagy.”

https://www.sciencedirect.com/science/article/abs/pii/S0040816626004490?via%3Dihub

Exploratory Prospective Study of Self-Titrated Medical Cannabis for Nonmotor Symptoms in Parkinson’s Disease

Posted on by

“Background: Medical cannabis (MC) has emerged as a potential therapy for Parkinson’s disease (PD), targeting motor and nonmotor symptoms (NMS), such as pain, sleep disturbance, and urinary dysfunction. Cannabinoid receptors in central and peripheral systems, including the bladder, provide a mechanistic basis for symptom modulation. This study evaluated the feasibility, safety, and preliminary clinical effects of MC on NMS in PD within a real-world, regulated framework.

Methods: In this single-center, open-label, prospective cohort, 68 patients with PD initiating MC were assessed at baseline and at 3 months using validated scales: the Non-Motor Symptoms Scale (NMSS), King’s Parkinson’s Disease Pain Scale (KPPS), PD Sleep Scale-2 (PDSS-2), PD Quality-of-Life Questionnaire-8 (PDQ-8), and International Prostate Symptom Score (IPSS), along with 2-day urinary diaries. Participants used either cannabis oil extract or inflorescence products with varying THC/CBD (Δ9-tetrahydrocannabinol/cannabidiol) ratios. Adverse events and withdrawals were recorded. Cannabinoid composition was analyzed via ultra-high-performance liquid chromatography and correlated with clinical outcomes.

Results: Fifty participants (mean age 65.6 ± 11.0 years; 68% male) completed follow-up. MC use was associated with improvements in NMSS total (Δ 14.5, p = 0.001), PDSS-2 (Δ 5.9, p < 0.001), KPPS (Δ 8.1, p = 0.004), PDQ-8 (Δ 1.5, p = 0.040), and the NMSS urinary domain (Δ 2.1, p = 0.050). Nighttime urinary frequency decreased (median Δ 0.5, p = 0.016), while daytime parameters were unchanged. No correlations were found between cannabinoid composition or THC/CBD enrichment type and clinical response. The dropout rate was 26.5%, mainly due to loss to follow-up.

Conclusions: Short-term, self-titrated MC was feasible and appeared generally well tolerated in this open-label setting, suggesting potential benefits for pain, sleep, and nocturnal urinary frequency in PD. These exploratory findings warrant randomized controlled trials focused on these domains and incorporating standardized dosing, pharmacokinetic monitoring, and predefined cognitive safety assessments to determine efficacy, safety, and optimal dosing.”

https://pubmed.ncbi.nlm.nih.gov/42304702

https://journals.sagepub.com/doi/10.1177/25785125261458680

Cannabidiol Protects Against 1-Methyl-4-Phenylpyridinium and Manganese-Induced Neurotoxicity via Nod-Like Receptor Protein 3 Inflammasome Suppression

Posted on by

“Parkinson’s disease (PD) is a neurodegenerative disorder characterized by dopaminergic neurodegeneration, alpha-synuclein (α-Syn) accumulation, and neuroinflammation. The NOD-Like Receptor (NLR) family pyrin domain containing 3 NLRP3 inflammasome has recently been identified as a central mediator of PD-associated inflammatory responses.

Cannabidiol (CBD), a non-psychoactive phytocannabinoid, exhibits anti-inflammatory and neuroprotective properties; however, its effects on NLRP3 inflammasome in PD remain insufficiently understood.

This study investigated the neuroprotective effects of CBD-rich oil against 1-methyl-4-phenylpyridinium (MPP+) and manganese-induced neurotoxicity in SH-SY5Y cells.

Cells were exposed to these substances with or without CBD co-treatment, and cell viability, α-Syn, dopamine, inflammatory markers [C reactive protein (CRP) and interleukin 18 (IL-18)], and NLRP3 expressions were evaluated.

MPP+ and manganese exposures significantly decreased cell viability and dopamine levels while increasing α-Syn accumulation and inflammatory markers. Manganese induced an approximately twofold upregulation in NLRP3 mRNA and 1.5-fold increase in protein expression.

CBD co-treatment preserved dopamine levels, attenuated α-Syn accumulation, reduced IL-18 and CRP concentrations, and attenuated NLRP3 expression.

These findings demonstrate that CBD-rich oil exerts neuroprotective effects in a PD cellular model by attenuating α-Syn accumulation, preserving dopamine homeostasis, which is associated with reduced NLRP3 expression and potential modulation of inflammasome-related signaling, supporting further investigation of CBD as a potential therapeutic strategy for PD.”

https://pubmed.ncbi.nlm.nih.gov/42262723

“There is growing interest in phytocannabinoids as potential interventions for neurodegenerative disorders. Cannabidiol (CBD), a non-intoxicating constituent of Cannabis sativa, exhibits neuromodulatory and neuroprotective properties, including anti-inflammatory and antioxidant effects mediated through multiple molecular targets relevant to basal ganglia function and PD symptomatology.”

“Accordingly, the present study investigated the neuroprotective potential of CBD-rich oil in an in vitro PD model using SH-SY5Y cells exposed to MPP+ and/or manganese.”

“In conclusion, CBD-rich oil mitigated multiple PD-relevant pathological features in a neurotoxicant-based cellular model. CBD reduced α-synuclein accumulation, preserved dopamine content, attenuated inflammatory markers, and was associated with reduced NLRP3 expression at both mRNA and protein levels. These findings support CBD as a potential neuroprotective agent and suggest that NLRP3 modulation may be a contributing mechanism.”

https://onlinelibrary.wiley.com/doi/10.1002/jbt.70957

Cannabidiol and other non-psychotropic cannabinoids from Cannabis sativa as therapeutics for microglial-mediated neuroinflammation and neurodegeneration

Posted on by

“Non-psychotropic phytocannabinoids produced by Cannabis sativa, including cannabidiol, cannabigerol, cannabichromene and their varin and acidic analogs, are emerging as promising modulators of neuroinflammation, particularly through actions on microglia, the brain’s resident immune cells.

These compounds engage numerous receptors, ion channels, and intracellular signaling systems in microglia associated with neuroinflammation, and therefore are promising therapeutic candidates to treat chronic microglial inflammation-mediated neurodegenerative disorders.

Despite substantial public and scientific interest, comprehensive evaluation of their mechanistic diversity, disease-relevant potential, and translational gaps across neurodegenerative disorders remains limited. Commonly, gaps also exist between cannabis breeders’ and cultivators’ knowledge of phytocannabinoid diversity and translational scientists’ understanding of therapeutic potential.

In this review, we first provide an in-depth overview of the main non-psychotropic phytocannabinoids, their biosynthesis, and the genetics that control their production in cannabis. We then summarize the known mechanisms of action for each cannabinoid in microglial-expressed molecular targets and signaling pathways relevant to neuroinflammation.

Lastly, we review the effects of non-psychotropic phytocannabinoids in pre-clinical models and clinical trials of four neuroinflammation-associated neurodegenerative diseases: Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and Huntington’s disease.

Current evidence supports meaningful biological activity and complex cannabinoid-specific polypharmacology, yet substantial gaps persist, especially for cannabinoids other than cannabidiol; addressing these gaps in disease-relevant models will be essential for translating these compounds into future therapeutic strategies. Further, we anticipate the summarized information will foster collaboration between cannabis breeders/cultivators and applications scientists for therapeutic evaluation and development of emerging non-psychotropic phytocannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/42121212

https://link.springer.com/article/10.1186/s42238-026-00445-5

The role of cannabinoid ligands in neurodegenerative diseases: emerging anti-inflammatory, immunomodulation and disease-modifying perspectives

Posted on by

“Neurodegenerative diseases (NDs) constitute a growing global health burden driven by population aging and remain without disease-modifying therapies. Although chronic neuroinflammation and aberrant protein aggregation are widely recognized as shared pathological hallmarks of major NDs – including Alzheimer’s, Parkinson’s, Huntington’s diseases and multiple sclerosis – the causal relationships linking immunoinflammatory signaling to neurodegenerative progression remain contentious. Therapeutic strategies targeting neuroinflammation have thus far yielded limited clinical success, underscoring the need for mechanistically grounded and context-specific interventions.

The endocannabinoid system (ECS) is a key regulator of synaptic function, glial activity, and immune homeostasis in the central nervous system (CNS), and its dysregulation has been consistently reported in neurodegenerative settings. However, ECS alterations across NDs are heterogeneous and often disease- and stage-dependent, with conflicting findings regarding cannabinoid receptor expression, endocannabinoid tone, and functional outcomes.

Moreover, while preclinical studies demonstrate robust anti-inflammatory and neuroprotective effects of cannabinoid ligands, clinical translation has been constrained by issues of receptor specificity, psychoactive side effects, limited brain penetration, and an incomplete understanding of long-term ECS modulation.

In this Review, we critically evaluate current evidence linking ECS signaling to neuroinflammatory mechanisms in neurodegeneration, highlighting both convergent pathways and unresolved controversies. We discuss the translational implications of ECS-targeted strategies, including the development of selective receptor modulators, allosteric and/or bitopic/dualsteric ligands, and enzyme inhibitors, as well as emerging approaches to mitigate adverse effects and improve therapeutic precision.

By integrating mechanistic insights with clinical challenges, this Review delineates key obstacles and opportunities for advancing ECS-based interventions toward disease-modifying therapies for neurodegenerative disorders.”

https://pubmed.ncbi.nlm.nih.gov/41937092

“These findings are particularly relevant for the development of next-generation cannabinoid therapeutics designed to selectively engage beneficial signaling pathways while minimizing adverse effects.”

https://www.sciencedirect.com/science/article/pii/S1043661826001003?via%3Dihub


Radical Revelations: The Interplay of Nitrosative Stress, the Endocannabinoid System, and Treatment of Age-Related Disorders

Posted on by

“The crosstalk between the endocannabinoid system (ECS) and reactive nitrogen species (RNS) has emerged as an important area of investigation in recent years.

Although many aspects of this interaction remain elusive, accumulating evidence demonstrates that the ECS plays a critical role in regulating RNS-mediated signaling under physiological conditions. This modulation can be either inhibitory or stimulatory, depending on the specific receptor subtype, cell type, and tissue location involved.

While ECS-RNS interactions support normal cellular homeostasis, their dysregulation contributes to various disease states, particularly neurodegenerative disorders. Studies in both rodent models and human subjects show that ECS modulation can reduce anxiety, attenuate neuroinflammatory responses, and slow disease progression in neurodegenerative conditions.

This review examines how cannabinoid-based interventions modulate nitrosative stress and neuroinflammation in Alzheimer’s disease (AD) and Parkinson’s disease (PD), highlighting their potential as targeted therapeutics that address multiple pathological mechanisms simultaneously and may offer advantages over conventional treatment approaches.”

https://pubmed.ncbi.nlm.nih.gov/41898672

“cannabinoid treatment offers a promising alternative to conventional treatments by addressing symptomology and the underlying molecular mechanisms of these diseases. Cannabinoid treatment uniquely addresses AD and PD pathology via crosstalk between the RNS and ECS, which provides hope for disease modification as an alternative to/supplement to conventional treatments.”

https://www.mdpi.com/1422-0067/27/6/2813


Cannabinoids and cognition in Parkinson’s disease: Insights from animal models and emerging clinical evidence

Posted on by

“Parkinson’s disease (PD) is a progressive, multisystem neurodegenerative disorder characterized not only by motor impairments but also by a broad spectrum of debilitating non-motor symptoms, including cognitive decline. The cognitive function depends on neuronal plasticity, which is tightly regulated by multiple signaling systems, among which the endocannabinoid system (ECS) plays a significant role.

Over the past three decades, substantial evidence has accumulated regarding how endogenous cannabinoids, plant-derived cannabinoids, and pharmacological modulators of ECS signaling influence synaptic plasticity, neuronal excitability, and neuroinflammation – processes that are critical in PD pathophysiology.

This narrative review synthesizes experimental and clinical evidence on the effects of cannabinoid compounds on cognition in preclinical PD models and patients. Available clinical data are limited, heterogeneous, and often underpowered, with cognition frequently assessed as a secondary outcome. Observed variability in cognitive effects likely reflects differences in cannabinoid formulation, dose and treatment duration, study design, patient characteristics, and the use of heterogeneous cognitive endpoints across studies.

Cannabinoid-based interventions hold promise for preserving neural circuits and modulating cognitive function in PD; however, well-designed, mechanism-informed trials with standardized, domain-specific cognitive endpoints are essential before clinical recommendations can be made.”

https://pubmed.ncbi.nlm.nih.gov/41864320

“Endocannabinoid system participates in cognitive modulation in Parkinson’s disease.”

https://www.ibroneuroscience.org/article/S0306-4522(26)00197-1/abstract

Involvement of Keap1/Nrf2 and the antioxidant defence in cytoprotective effects induced by cannabis polyphenols in SH-SY5Y neuronal cells

Posted on by

“Oxidative stress (OS) is widely recognized as a central promoter to the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS).

Cannabis sativa L. synthesizes a complex array of bioactive compounds that extends well beyond the well-known cannabinoids to include a diverse suite of polyphenols, terpenes, fatty acids, tocopherols, and proteins. The non-cannabinoid polyphenolic fraction is composed primarily of flavonoids, stilbenoids, lignans, and lignanamides, which contribute substantially to the plant’s antioxidant, anti-inflammatory, and neuroprotective properties.

This study investigates the redox-modulating and cytoprotective properties of a polyphenolic fraction derived from Cannabis sativa L. in SH-SY5Y neuroblastoma cells.

Neurons were treated with various concentrations of the aqueous polyphenolic cannabis extract and exposed to oxidative stress using hydrogen peroxide (100 µM). Protein and gene expression related to redox signalling were analyzed via Western blot and qPCR, and molecular docking studies were performed in silico. Furthermore, antioxidant enzymes activity was measured by spectrophotometry.

Results revealed that the phenolic fraction significantly activated the Keap1/Nrf2 pathway, increased expression of PRDX1 and PRDX3, and enhanced endogenous antioxidant defences. Simultaneously, it reduced endoplasmic reticulum stress-induced apoptosis (via Bax/Bcl-2 modulation) and attenuated inflammatory markers, including NO, NF-κB2, IL-6, and IL-8. In silico docking studies identified Leu583 as a key residue in Nrf2-ligand interactions.

These findings suggest that Cannabis sativa L. polyphenols are key bioactive compounds modulating redox homeostasis and inflammation, and offering neuroprotective benefits with potential relevance in diseases involving mitochondrial dysfunction and oxidative damage.”

https://pubmed.ncbi.nlm.nih.gov/41643607

“Collectively, these results position phenolic compounds present in Cannabis sativa as promising and essential key candidates for targeting mitochondrial dysfunction and oxidative neurotoxicity, although further studies are needed to fully the therapeutic and clinical potential.”

https://www.sciencedirect.com/science/article/pii/S0753332226000806?via%3Dihub

Unveiling Neurological Benefits: A Review of Hemp Leaf, Flower, Seed Oil Extract, and Their Phytochemical Properties in Neurological Disorders

Posted on by

“Neurological disorders such as epilepsy, Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis present significant global health care challenges, with complex pathophysiology and limited therapeutic options that often carry substantial side effects.

Hemp-derived compounds, particularly from Cannabis sativa seeds, leaves, and flowers, have gained attention for their potential neuroprotective properties.

This review aims to synthesize the current evidence surrounding the therapeutic benefits of hemp-derived compounds, focusing on their bioactive phytochemical profiles, mechanisms of action, and therapeutic efficacy in treating neurological disorders.

A comprehensive review of pre-clinical and clinical studies was conducted, analyzing the phytochemical composition of hemp extracts, including cannabinoids (such as cannabidiol, CBD), terpenes, flavonoids, and polyunsaturated fatty acids. We explored their mechanisms of action through interactions with the endocannabinoid system, neurotransmitter receptors, inflammatory pathways, and oxidative stress mechanisms.

The review highlights the therapeutic potential of hemp-derived extracts in mitigating various neurological conditions. Pre-clinical and clinical studies have demonstrated their efficacy in reducing seizure frequency in epilepsy, protecting dopaminergic neurons in Parkinson’s disease, alleviating neuroinflammation and oxidative stress in Alzheimer’s disease, and promoting remyelination in multiple sclerosis.

The entourage effect, where cannabinoids, terpenes, and flavonoids work synergistically, enhances these therapeutic effects. Innovations in extraction technologies have optimized yield and preserved bioactivity, further enhancing clinical relevance.

Hemp-derived compounds exhibit significant neuroprotective and therapeutic potential for managing neurological disorders. However, challenges such as product standardization, safety profiles, and regulatory frameworks must be addressed for clinical translation. Further research is essential to optimize dosing, establish safety parameters, and develop standardized formulations, which will be crucial for fully harnessing the therapeutic potential of hemp-derived products in treating neurological conditions.”

https://pubmed.ncbi.nlm.nih.gov/41468178

https://www.liebertpub.com/doi/10.1177/25785125251410822


Cannabidiol as a Neuroprotective Agent in Acrylamide-Induced Neurotoxicity: Effects on Oxidative Stress, Inflammation, and Cholinergic Function in Male Mice

Posted on by

“The neuroprotective potential of cannabidiol (CBD) was assessed in a mouse model of acrylamide-induced neurotoxicity.

Acrylamide (AA), an environmental and dietary pollutant, is known to cross the blood-brain barrier and induce oxidative stress, inflammation and neurotoxic effects.

Male C57BL/6 mice were randomly assigned to four groups: Control (Con), Acrylamide (AA), Cannabidiol (CBD), and a combination treatment (AA + CBD). The AA group received acrylamide (10 mg/kg, i.p.) daily for 5 days. CBD was administered (10 mg/kg, i.p.) for 10 days in the CBD and AA + CBD groups. In the AA + CBD group, acrylamide (10 mg/kg, i.p.) was co-administered during the last 5 days of CBD treatment.

Behavioral outcomes were analyzed using the open field test, revealing that CBD mitigated anxiety-like behavior induced by acrylamide, enhancing movement and center exploration. Further, CBD treatment modulated oxidative stress responses, reducing MDA levels and partially restoring antioxidant markers (GSH, SOD, and CAT) in the hippocampus and striatum. Inflammatory markers were also assessed, revealing that acrylamide elevated pro-inflammatory cytokines TNF-α and IL-6.

Notably, CBD co-treatment reduced TNF-α levels in the hippocampus and cortex and attenuated IL-6 levels in the cortex and striatum, suggesting an anti-inflammatory effect. Additionally, CBD modulated neuroplasticity by increasing BDNF levels in the hippocampus, counteracting the reduction caused by acrylamide. CBD also influenced cholinergic activity by restoring Ach levels and altering AChE activity across brain regions.

Findings suggest that CBD exhibits neuroprotective properties by reducing oxidative stress, inflammation and cholinergic dysregulation, thereby offering a promising therapeutic approach for mitigating pollutant-induced neurotoxicity and potentially treating neurodegenerative disorders.”

https://pubmed.ncbi.nlm.nih.gov/41395773

“By improving behavioral outcomes, reducing oxidative stress, modulating inflammation, enhancing neuroplasticity and preserving cholinergic function, CBD shows promise as a potential therapeutic approach for neurotoxic and neurodegenerative conditions. “

https://onlinelibrary.wiley.com/doi/10.1002/jnr.70098